Brains can perform complex functions by generating a systemic neural network through a series of processes, including the division, differentiation, survival and death of neuronal stem cells and the formation of synapses. Such brains have a low ability to regenerate, compared to other organs, and thus damage to the brain can result in serious sequelae. Particularly, the occurrence of a tumor in the brain can cause significant damage to the brain, resulting in a significant reduction in the survival rate of the patient. The most effective conventional method for treating brain tumors is the resection of brain tumors by a surgical operation. However, depending on the type and location of brain tumor, it is impossible to perform a surgical operation, and complete resection of brain tumors by surgery presents a high risk of complications. In addition, in chemotherapy with anticancer drugs, administration of a high concentration of anticancer drugs is required due to the presence of the blood-brain barrier, thus causing serious side effects.
In attempts to overcome such problems, gene therapy methods have been proposed that use viruses to introduce genes, which inhibit the proliferation of cancer cells, directly into the cancer cells. However, it was actually impossible to introduce viruses even into a minute tumor or cancer tissue. Also, conventional methods, including viral surface modification and magnetic transfer techniques, had limitations in targeting minute cancer tissue. Additionally, the problems according to the immune toxicity of viruses are still raised.
In recent years, as the affinity of stem cells (including neural stem cells and mesenchymal stem cells) for brain tumors has been known, a possibility to stem cells as a gene delivery medium has been proposed (Aboody et al., Proc. Natl. Acad. Sci. USA, 97:12846, 2000; Brown et al., Human Gene Therapy, 14:1777, 2003; Tang et al., Human Gene Therapy,14:1247, 2003; Zhang et al., Neurolmage, 23:281, 2004; Nakamura et al., Gene Therapy, 11:1155, 2004; Zhang et al., Neurolmage, 23:281, 2004). Particularly, with respect to methods for treating brain tumors using such stem cells, it was reported that, when neural stem cells expressing cytosine deaminase (CD) that is the E. coli suicide gene were used to target glioma, excellent anticancer effects were shown (Aboody et al., Proc. Natl. Acad. Sci. USA, 97:12846, 2000; Brown et al., Human Gene Therapy, 14:1777, 2003). Also, Korean Patent Laid-Open Publication No. 10-2007-0036289 discloses a composition for treating cancer comprising mesenchymal stem cells expressing a suicide gene.
However, the above-described methods have a problem in that they are not effective for the treatment of cancer, because cancer cells are targeted at a low level. In addition, these methods are inefficient, because craniotomy should always be performed in order to introduce neural stem cells expressing a suicide gene. Meanwhile, the above-described literature showed only the affinity of stem cells for brain tumors, but did not present a method for delivering neural stem cells to brain tumor sites, based on the discovery of a substance that causes the affinity.
Meanwhile, periostin that is also called “OSF-2” is a protein originally isolated from osteoblasts and is known to be involved in the replacement, adhesion and spreading of osteoblasts (WO/2005/062055). It causes mature cardiac cells to divide, thus inducing the production of new cardiac cells. Also, it is known that periostin is tissue-specifically expressed in the periosteum and periodontal ligament and that the expression is regulated by TGF-beta (Johnson & Lancero, 1999). Also, the possibility of periostin as a cancer metastasis marker has been reported (Wei Wan & Rong Shao, J. Biol. Chem., 281(28):19700, 2006). Periostin is known as a protein that is secreted from various cancer cells. Specifically, periostin has been reported to be secreted from small intestinal and colon cancer cells (Bao et al., 2004), breast cancer cells (Shao et al., 2004), lung cancer cells (Sasaki et al., 2001), pancreas cancer cells (Baril et al., 2007) and ovarian cancer cells (Gillan et al., 2002). Also, it was reported that the expression of periostin increased to facilitate the differentiation of endothelial cells in damaged cardiac tissue and the migration of endothelial cells to the damaged site (Lindner et al., 2005) and also that periostin is involved in the metastasis, invasion, propagation and survival of cancer cells (Kanno et al., 2008). However, it has not yet been reported that periostin has a function of inducing the migration of neural stem cells.
Accordingly, the present inventors have made extensive efforts to provide a substance for inducing the migration of neural stem cells so that a cell therapeutic agent for inducing cancer cell death can be prepared, which has enhanced efficiency, and can be used in studies on neural stem cells in various fields. As a result, the present inventors have found that periostain isolated from tumor tissue has the ability to induce the migration of neural stem cells, thereby completing the present invention.